Ketone ester supplementation in aged mice produces sex-specific cognitive and metabolic effects

The ketogenic diet (KD) elevates β-hydroxybutyrate (β-HB), an energy metabolite and signaling molecule with immunomodulatory effects, and has been associated with cognitive and metabolic effects in some preclinical and clinical studies. However, clinical evidence for ketogenic and ketone-based interventions in cognitive aging and Alzheimer's disease remains mixed, and long-term carbohydrate restriction may be difficult to implement in older adults. Dietary supplements that elevate β-HB, such as medium-chain triglycerides and ketone esters, have been proposed as alternatives to the KD, but their sex-specific effects in aging remain poorly defined. Here, we determined the effects of short-term supplementation with the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate on physical function, metabolism, and age-related memory outcomes in 24-month-old male and female C57BL/6 mice. The ketone ester-containing diet increased postprandial β-HB and lowered postprandial glucose; however, its effects on cognitive, anthropometric, inflammatory, and metabolic outcomes differed by sex. In males, the intervention changed body composition, with lower body fat and higher relative lean mass. In females, the intervention was associated with fewer Barnes maze primary errors and lower hippocampal IL-1β expression. These sex-dependent effects were accompanied by differences in fasting metabolite profiles across tissues and biofluids and by altered hippocampal oxylipins. Further studies are needed to determine whether ketone monoester supplementation has similar sex-specific effects in humans, and to define the mechanisms, physiological changes, and translational relevance of ketone-based interventions in aging.